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Harald Gollnick

Publications and source records attributed to Harald Gollnick.

At least 37 records · Page 2Linked to original sources
PubMed2004

Identification of extra- and intracellular alanyl aminopeptidases as new targets to modulate keratinocyte growth and differentiation.

Aminopeptidase inhibitors strongly affect proliferation, differentiation, and function of immune cells and show therapeutic potential in inflammatory disorders. In psoriatic lesions, keratinocytes display increased cellular turnover and disturbed differentiation, leading to epidermal hyperplasia accompanied by the loss of stratum granulosum. Here, we report in the HaCaT hyperproliferative keratinocyte cell line as well as in two primary keratinocyte strains in vitro a molecular and biochemical analysis of the expression of both membrane and cytosol alanyl aminopeptidase (cAAP) on the mRNA, protein, and enzymatic activity level. We found a clear dose-dependent suppression of DNA synthesis in vitro in the presence of the inhibitors actinonin, bestatin, and the cAAP-specific inhibitor PAC-22 correlating well with the simultaneous decrease in enzyme activity. In vivo, actinonin dose-dependently restored the stratum granulosum and ameliorated the impaired keratinocyte differentiation in the mouse tail model of psoriasis. Taken together, these data suggest that targeting alanyl aminopeptidases may be beneficial for psoriasis and other inflammatory skin disorders.

Animals↗
PubMed2004

Molecular interactions of B-CAM (basal-cell adhesion molecule) and laminin in epithelial skin cancer.

Molecular events underlying the progression of malignant tumors through the surrounding tissue are largely mediated by membrane-bound adhesion molecules. Basal-cell adhesion molecule (B-CAM), a 90-kDa laminin receptor of the immunoglobulin superfamily, is induced in some epithelial malignancies. Its function in these tumors, however, still remains obscure. We demonstrated that expression of B-CAM is very weak, if detectable at all, in normal epidermis but is strongly induced in both basal cell carcinomas and squamous cell carcinomas of the skin, and most pronounced at the basal surface of the tumor nests. Interestingly, the only known B-CAM ligand, laminin, was markedly upregulated within corresponding microanatomical sites surrounding the tumor nests, suggesting that both molecules may interact there. Consistent with this hypothesis, we were able to directly demonstrate binding of a B-CAM/Fc chimeric molecule to the peritumoral stroma in situ. Finally, in proof-of-principle experiments, human B-CAM was overexpressed both in murine and in human fibroblasts. The haptotactic migration of these novel B-CAM+ cell populations on a laminin matrix was significantly increased (P = 0.02) as compared to mock-transfected cells when integrin-mediated adhesion was blocked by chelation of divalent cations. Thus, our findings provide the first direct experimental evidence that interactions of B-CAM and laminin may be involved in progression of epithelial skin tumors.

Animals↗
PubMed2004

A novel flow cytometric assay focusing on perforin release mechanisms of cytotoxic T lymphocytes.

CD8(hi+) cytotoxic T lymphocytes (CTL) are major players in immune defense. In addition, they contribute to the maintenance of immune homeostasis. We now describe a hitherto unavailable, but simple assay to determine ex vivo lytic granule-based cytotoxic functions of human CD8(hi+) CTL subgroups in a clinical setting, under target cell free conditions. Ficoll-isolated peripheral blood lymphocytes from 17 healthy volunteers were stimulated either by phorbol 12-myristate 13-acetate (PMA) in combination with ionomycin or by antibody mediated crosslinking of the CD3 molecule on the T cell surface. Using perforin as a marker for lytic granules, the reduction of CTL granules over time intervals up to 120 min was quantified by FACScan flow cytometry. The kinetics of perforin reduction were compared to the kinetics of NA-CBZ-L-lysine-thiobenzyl ester hydrochloride (BLT)-esterase release and of CD63 upregulation. The reduction in the perforin(+) portion of CD8(hi+) CTLs was correlated inversely with BLT-esterase release and CD63 upregulation. At 30 and 120 min after PMA/ionomycin stimulation, 55 +/- 14% and 42 +/- 14%, respectively, of CD8(hi+) CTLs still stained perforin(+) (time point 0 min = 100%). Perforin-granule release induced by CD3-crosslinking occurred as fast within 30 min (55 +/- 17%), but over the 120 min time interval it was not as complete when compared to PMA/ionomycin-stimulated perforin-reduction. Thus, the combination of an established degranulation assay with the power of immuno flow cytometry allows one to investigate the cytotoxic capability of CTL-subtypes and the kinetics of perforin-granule release. In addition, the assay may prove useful in the elucidation of intracellular signaling cascades governing the perforin-granule release process.

Biological Assay↗
PubMed2004

Imiquimod, a Toll-like receptor-7 agonist, induces perforin in cytotoxic T lymphocytes in vitro.

Imiquimod (IMQ), an activator of Toll-like receptor-7 (TLR-7), induces by several routes a profound anti-viral and anti-tumor effect in vivo. Physiologically, the immune system is using perforin-containing granules of cytotoxic T lymphocytes (CTL) towards the same biological purpose. This functional synergism prompted our current experiments addressing the question whether IMQ may influence perforin-release and/or induce perforin in CTLs in vitro. In peripheral lymphocytes of healthy and diseased subjects, IMQ induced a significant increase of perforin(+) CTLs within 12h in all experiments performed. This effect was most pronounced in CTLs of patients suffering from atopic dermatitis, a model disorder for subnormal perforin expression: as compared to perforin(+) CTLs detected at time point zero (100%), up to 270% of perforin(+) CTLs were induced by 2.5 microg/ml [corrected] IMQ. Perforin release from peripheral blood CTLs after PMA/ionomycin-stimulation was not influenced significantly by IMQ. Thus, the biological activity of IMQ appears to exceed its previously known functions, inasmuch as it boosts up significantly the perforin-granule system.

Adjuvants, Immunologic↗
PubMed2004

[DRGs in dermatology: results of the DRG evaluation project of the German Society of Dermatology (DDG)].

SUMMARY BACKGROUND: The implementation of a DRG system in Germany--voluntarily since January 1st, 2003, and obligatory after January 1 st, 2004--has led to uncertainty, particularly in the hospitals. There are fears that current well-accepted German diagnostic and therapeutic services may not be properly financed by the new system. In response, the German Dermatologic Society (DDG) in cooperation with the DRG Research Group of the University Hospital Muenster and the German Medical Association carried out a DRG evaluation project in order to investigate the medical and economic homogeneity of the case groups. PATIENTS AND METHODS: 19,403 dermatological cases from 19 hospitals--ten university hospitals and nine non-university hospitals-were collected over a period of four months and then evaluated with regard to their performance, length of stay and cost homogeneity. RESULTS: The data provided the background needed to indicate suspected potential deficiencies for mapping dermatology cases within the German DRG system. Based on the data 10 modifications were formulated and submitted to the InEK by the deadline of March 31st, 2003. CONCLUSIONS: The results of the DRG Evaluation Project show that the G-DRG-Variant Version 1.0 does not offer the necessary possibilities of differentiation to map the broad spectrum of various dermatology services in Germany.

Cost-Benefit Analysis↗
PubMed2004

[Photodynamic therapy with methylaminooxopentanoate (Metvix) and a broad band light source (PhotoDyn 501): practical experiences in problem-patients with actinic keratoses and basal cell carcinomas].

BACKGROUND: Actinic keratoses (AK) and basal cell carcinomas (BCC) may represent a therapeutic challenge because of special subtypes, location, previous therapy or accompanying diseases. Photodynamic therapy (PDT) offers a semi-conservative treatment option for selected indications. PATIENTS AND METHODS: 28 outpatients who had been admitted as complicated dermato-oncologic cases because of AK (n = 22) and BCC (n = 6) were treated with PDT, using methylaminooxopentanoate (MAOP, Methyl-Ala, Metvix) and a broad band light source (PhotoDyn 501). The treatment was evaluated for efficacy and subjective tolerance (local discomfort and pain). RESULTS: A complete remission (CR) was achieved in 11/22 AK (50%) and 4/6 BCC (67%) cases. All three cases of a superficial BCC subtype underwent a CR. Among responders, tolerance was good in 12/15 cases (80%), as compared to 4/13 cases (31%) in non-responders. Focusing on 16/28 patients with good tolerance (57%), there was a CR in 12 cases (75% rate), whereas for the 12/28 patients with moderate to poor tolerance a CR was achieved in only 3 cases (25% rate). In a subgroup of 8 patients who, partly due to secondary diseases, were taking systemic retinoids or immunosuppressive-cytostatic medications, a CR was achieved in 3/8 cases (38%) with a good tolerance in only 1/8 cases (13%). CONCLUSION: These observations confirm a good efficacy and tolerance of PDT in > or = 50% of a AK/BCC problem patient cohort. We found indications for 1) a positive correlation between efficacy and subjective tolerance as well as 2) the presumptive existence of a retinoid-dependent cutaneous PDT hyperalgesia. Effective pain control seems to be an essential cofactor for the success of PDT.

Aged↗
PubMed2004

Death receptor-independent apoptosis in malignant melanoma induced by the small-molecule immune response modifier imiquimod.

Bypassing molecular mechanisms of apoptosis deficiency may be of great utility for the successful treatment of malignant tumors. We have discovered that imiquimod, a small-molecule immunomodulator, exerts rather tumor-selective direct pro-apoptotic activity in vivo and in vitro towards cutaneous metastases of malignant melanoma, an aggressive skin tumor. This pro-apoptotic activity was not detectable with resiquimod, a closely related structural analogue whose pro-inflammatory activity is even greater than that of imiquimod. Unresponsiveness of some melanoma metastases to imiquimod in vivo corresponded to resistance towards imiquimod-induced apoptosis in vivo and in vitro. At the molecular level, the pro-apoptotic activity of imiquimod was independent of membrane-bound death receptors, but depended on Bcl-2 expression as demonstrated by overexpression of Bcl-2 in melanoma cells. Imiquimod is the first topical compound with the potential to bypass molecular mechanisms of apoptosis deficiency, a concept that may be relevant for other tumors as well.

Administration, Topical↗
PubMed2004

Antipruritic effects of two different 5-HT3 receptor antagonists and an antihistamine in haemodialysis patients.

Pruritus is the most distressing symptom in haemodialysis (HD) patients. Its aetiology has not yet been delineated, and thus there are no good therapeutical options. Case reports and series attribute antipruritic potency to the serotonin receptor antagonists of the 5-HT3 type in renal pruritus. It was the aim of this study to investigate the antipruritic effect of two different 5-HT3 receptor antagonists and an antihistamine in 11 patients undergoing HD. Pruritus was induced by iontophoresis with serotonin and histamine and recorded before and after HD. These data were compared to those obtained after oral pretreatment with the 5-HT3 receptor antagonists tropisetron 5 mg and ondansetron 8 mg and the antihistamine cetirizine 10 mg. Ten healthy volunteers served as a control group. Vasocutaneous parameters (wheal and flare), skin temperature and alloknesis were also determined. Itching in HD patients and controls was not significantly diminished by oral pretreatment with the serotonin receptor antagonists. In controls, but not in HD patients, cetirizine significantly reduced itching, skin temperature and vasocutaneous parameters. Our data additionally demonstrate that there are no significant differences in vasocutaneous parameters, itching and alloknesis in HD patients before and after dialysis. We conclude that 5-HT3 receptor blockers such as tropisetron and ondansetron and the antihistamine cetirizine do not sufficiently reduce serotonin- and histamine-induced itching in haemodialyis patients.

Adult↗
PubMed2004

Superiority of a combined contraceptive containing drospirenone to a triphasic preparation containing norgestimate in acne treatment.

This double-blind study compared the efficacy and tolerability of a combined oral contraceptive containing 30 microg ethinyl estradiol and 3 mg drospirenone (EE/DRSP; Yasmin) with a triphasic preparation containing 35 microg EE and 0.180, 0.215, 0.250 mg norgestimate (EE/NGM; Pramino, also known as Ortho Tri-Cyclen) in the treatment of acne vulgaris. The combined presence of antiandrogenic and antimineralocorticoid activities of drospirenone is unique to this novel progestin in that these characteristics most closely resemble those of progesterone. The study was designed to show that EE/DRSP was noninferior or superior to EE/NGM as to the relative decrease from baseline to cycle 6 in percentage of inflammatory and total lesion counts and the investigators' assessment of acne improvement. Other outcomes included subjects' assessment of therapeutic effect, sebum production, and hormone levels. Female subjects were randomized to EE/DRSP (n = 568) or EE/NGM (n = 586) for 6 treatment cycles, consisting of 21 consecutive days of hormone intake, followed by 7 hormone-free days. The preparation containing EE/DRSP was superior to EE/NGM for reduction in total lesion count (-3.3% in favor of EE/DRSP [95% CI, -6.5 to -0.1; P = .020]) and for investigators' assessment of therapeutic effect on facial acne (+3.6% in favor of EE/DRSP [95% CI, 0.8 to 6.3; P = .006]). The 2 preparations were comparable as to their decreases in inflammatory lesion count. Evaluation of the effect of treatment by subjects was consistent with that of the investigators. Furthermore, both preparations increased the level of sex hormone-binding globulin (SHBG) and decreased the levels of androgens, changes typically associated with acne improvement. Both preparations were well tolerated. In conclusion, owing to the unique pharmacologic activities of drospirenone, the combined oral contraceptive EE/DRSP provides an effective treatment option in female patients with mild to moderate acne.

Acne Vulgaris↗
PubMed2004

[Sarcoidosis, myasthenia gravis and anterior ischaemic optic neuropathy: severe side effects of adjuvant interferon-alpha-therapy in malignant melanoma?].

In dermato-oncology, interferon-alpha is widely used as treatment of cutaneous lymphoma and as adjuvant therapy in high risk malignant melanoma. With increasingly wide administration of interferon-alpha (IFN-alpha), not only early-onset side effects, such as influenza-like symptoms, but also uncommon late-onset side effects are being recognized. We present three patients with melanoma who developed rare side effects in the course of adjuvant IFN-alpha-therapy: sarcoidosis, myasthenia gravis and anterior ischaemic optic neuropathy. Based on current knowledge a causal relationship between these diseases and the administration of IFN-alpha can neither be affirmed or absolutely ruled out. Therefore special attention should be paid to such coincidences.

Aged↗
PubMed2003

Tumor-selective induction of apoptosis and the small-molecule immune response modifier imiquimod.

BACKGROUND: The incidence of nonmelanoma skin cancer, basal cell carcinomas (BCCs), and squamous cell carcinomas (SCCs) is increasing, representing a major medical and economic problem. Imiquimod, a topical small-molecule immune response modifier, has shown efficacy toward BCC and actinic keratoses in clinical trials. Imiquimod acts both indirectly, via cytokine-mediated stimulation of cellular immune responses, and directly, through unknown mechanisms against tumor cells. We examined the mechanism by which imiquimod induces apoptosis in cancer cells. METHODS: Apoptosis was assessed by enzyme-linked immunosorbent assay, western blot analysis, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays in five SCC cell lines, HaCaT cells (a spontaneously immortalized human keratinocyte cell line), and normal keratinocytes treated with imiquimod, with its analog resiquimod, or with neither. Expression of death receptors, caspases, and cytochrome c in the apoptotic signaling cascade was analyzed using western blot and flow cytometric analyses. The functional relevance of imiquimod-induced cytochrome c release was assessed by transfection of HaCaT cells with Bcl-2. Apoptosis in BCCs in vivo was assessed by TUNEL assays of imiquimod-treated and untreated tumors from three patients. Differences between treated and untreated cells and tumors were determined using a two-tailed Student's t test. RESULTS: Imiquimod, but not resiquimod, induced apoptosis in all SCC cell lines and HaCaT cells. This induction involved activation of several caspases and Bcl-2-dependent cytosolic translocation of cytochrome c but was independent of the membrane-bound death receptors Fas, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-R1-R4 receptors, and tumor necrosis factor-R1 and -R2 receptors. Topical application of imiquimod to BCC tumors in vivo induced apoptosis. CONCLUSION: Imiquimod has the potential to induce apoptosis in skin cancer cells, possibly by circumventing mechanisms developed by malignant tumors to resist apoptotic signals.

Aminoquinolines↗
PubMed2003

Topical capsaicin therapy in humans with hemodialysis-related pruritus.

As shown in previous experimental studies, topical capsaicin has a strong inhibitory effect in histamine-induced itch in healthy persons, but not in patients with atopic eczema. However, in serotonin-induced itch, it was not a sufficient antipruritic. Eleven pruritic patients on hemodialysis (HD) and ten controls were treated with capsaicin 0.05% liniment on the upper back three times daily for 5 days. Study parameters to be investigated were wheal and flare reactions, itch and alloknesis (perifocal itch sensation induced by usually non-itching stimuli) after serotonin and histamine iontophoresis in treated and untreated skin. There were no significant differences in any parameter before and after HD. In both groups, itching was not significantly reduced by capsaicin compared to untreated skin. Itching, however, was significantly lower in capsaicin-pretreated patients when comparing to controls. In summary, topical capsaicin showed some antipruritic potency in HD patients in this experimental model and may therefore be considered as a co-medication in HD patients.

Administration, Topical↗
PubMed2003

Lung carcinoma with congenital plantar keratoderma as a variant of Clarke-Howel-Evans syndrome.

A 32-year-old man was admitted to the Magdeburg University Hospital with icterus and for further diagnosis of suspected hepatitis. He also complained of generalized pruritus, abdominal pain, nausea, and diarrhea. The patient's history revealed the excision of a lymph node metastasis of the left groin showing pleomorphic macrocellular infiltrates, 2 months previously. The patient presented to our department with prominent hyperkeratosis of both feet, which had been present since early youth. The family history was negative. Both soles showed very thick, white and blackish hyperkeratosis with predominance of the heels and the forefeet (Fig. 1). The naturally occurring wrinkles of the skin of the toes were flattened. The palms were not affected, and neither was the oral mucosa. Further investigations revealed icterus of the sclera and multiple, firm tumors, which were located in the deep subcutaneous tissue, on the left hip, thigh, and buttock. From thorough clinical, laboratory and staging investigations, a non-small-cell bronchogenic carcinoma, with metastases of the liver, kidneys, adrenal glands, and several skin sites, was diagnosed. A skin biopsy specimen of the foot showed substantial acanthosis of the epidermis with hypergranulosis and excessive orthohyperkeratosis. The corneocytes were enlarged and arranged in a tile-like pattern (Fig. 2). The dermis was free of inflammatory infiltrates and human papillomavirus infection was ruled out by immunohistochemistry. Polychemotherapy was immediately started with 5-fluorouracil, mitomycin, and cisplatin, which was well tolerated. When the patient was admitted for the second cycle, however, his general health had worsened markedly. He complained of abdominal pain, severe weight loss, and nausea. Generalized metastases showed substantial progression. Chemotherapy could not be continued because of a Karnowsky index below 20%. The patient died 2 weeks later.

Adult↗